Odors play an increasingly appreciated role in our general quality of life and well being, a role that is compromised by the effect of disease, drugs, aging and environmental onslaught on the olfactory epithelium. As olfactory receptor neurons (ORNs) in the olfactory epithelium provide the primary input to the olfactory system, disruption of any of the cellular processes leading to the activation of the ORNs inevitably compromises impairs olfactory function. This project builds on our emerging understanding that the organization of the olfactory periphery is more complex than originally appreciated. It specifically addresses a largely ignored aspect of that complexity, which is how odorants are able to inhibit as well as excite ORNs. It tests the hypothesis, built on increasingly compelling data, that phosphoinositide (PI) signaling mediates inhibitory input to mammalian ORNs and plays an important role in setting the output of the ORNs evoked by natural, complex odorants. A series of focused, electrophysiological, biochemical, and molecular experiments address this question by continuing to evaluate the functional significance of PI signaling in rodent ORNs, and beginning to identify the cellular mechanisms through which PI signaling works. The idea that inhibitory input is mediated through a distinct input pathway from that mediating excitation represents important new insight into the sense of smell, insight that not only raises fundamental questions about the nature of the OR itself but also about the importance of inhibitory input to olfactory coding in having a separate signaling pathway assigned to it. PUBLIC HEALTH RELEVANCE: An estimated 1% of the population under the age of 65 and at least 50% of older individuals demonstrate detectable smell loss. Disruption of any of the cellular events by which odors activate olfactory receptor cells, such as the events that are the target of this research, disrupt olfactory input to the brain. A detailed understanding of how odors activate olfactory receptor cells therefore is critical to effectively address disease states such as dementia and the diminished quality of life associated with olfactory dysfunction.